The present invention relates to administration of medical powders into the respiratory tract by releasing an electrostatically dosed powder to be inhaled and more particularly to a method for optimizing the function of an electrostatically dosed dry powder inhaler (EDPI) in relation to a pre-metered dose of electro-powder.
Dosing of drugs is carried out in a number of different ways in the medical service today. Within health care more and more is focused on the possibility of dosing medical drugs as a powder directly to the airways and lungs of a user by means of an inhaler in order to obtain an effective, quick and user-friendly administration of such substances. But today the dosing quality is not good enough to be used for wide range of drugs. This is specially the case for systemic delivery by inhalation through a dry powder inhaler (DPI) which represents an important segment making it possible to compete with the injection needle for many types of drugs, i.e. insulin, pain management etc.
A dry powder inhaler of today, (DPI), represents a device intended for administration of powder into the deep or upper lung airways by oral inhalation. With deep lung should be understood the peripheral lung and alveoli, where direct transport of active substance to the blood can take place. Particle sizes, to reach into the deep lung, should be in a range 0.5-3 xcexcm and for a local lung delivery in the range 3-5 xcexcm. A larger grain size will easily stick in the mouth and throat, and a smaller grain size may accompany the expiration air out again.
To succeed with systemic delivery of medical powders to the deep lung by inhalation there are some criteria, which have to be fulfilled. The most important is a very high degree of de-agglomeration of the medical powder but also an exact dose is of great importance. This is not possible with dry powder inhalers of today without special arrangements as for example a so-called spacer.
By means of a spacer the small grains are evenly distributed in a container from which the inhalation can take place. Upon inhalation from the spacer the fine powder is floating free in the air and will effectively reach the alveoli""s of the lung. This method in principle has two drawbacks, firstly difficulties to control the amount of medicine emitted to the lung as an uncontrolled amount of powder sticks to the walls of the spacer and secondly difficulties in handling the relatively space demanding apparatus. It is also common to utilize carriers i.e. Lactose having a larger grain size onto which the fine power is distributed. Upon inspiration the large size grains will then stick in the oral cavity while the fine particle fraction, this is powder smaller than 5 xcexcm, will be let free and proceed to the lung. For instance U.S. Pat. No. 5,642,727 discloses a tribo-inhaler having a container portion for electrostatically retaining a predefined dose of medicament powder. The container portion contains a plurality of polymeric beads that have diameters of approximately 50 to 200 microns. Each of the polymeric beads has a specific quantity of dry powder medicament electrostatically adhered to its surface.
An American document U.S. Pat. No. 5,871,010 addresses an inhaler apparatus with modified surfaces for enhanced release of dry powders. The inhaler apparatus disclosed comprises interior surfaces having low surface energy for minimizing contact between a medicament and the surfaces of the inhaler to minimize deposition of the dry powder.
Powders for inhalers have a tendency of agglomerating, in other word to clod or to form small or larger lumps, which then have to be de-agglomerated. De-agglomeration is defined as breaking up agglomerated powder by introducing electrical, mechanical, or aerodynamic energy. Usually de-agglomeration is performed as a stage one during dosing and as a final stage two during the user""s inspiration through the DPI.
Inhaler devices normally use the force exerted by the user""s more or less normal inspiration effort for de-agglomerating the medical substance administered when inhaling in an effort to bring as much as possible of the active substance into the lungs. This often leads to inhaler designs using high pressure drops, which will put the user""s lungpower to the test.
Technologies to de-agglomerate today include advanced mechanical and aerodynamic systems and combinations between electrical and mechanical filling systems that can be seen in for instance in U.S. Pat. No. 5,826,633. Further there are systems disclosed for dispersing aerosolized doses of medicaments, e.g. U.S. Pat. Nos. 5,775,320, 5,785,049, and 5,740,794. Furthermore, in our International Publications WO 00/06236 and WO 00/06235 principles for de-agglomeration and classification are disclosed.
To meet some of these demands an electrostatic dosing of the powder onto a technical means for example a cassette can be done. An electrostatic dosing onto a device member or cassette was described in our Swedish Patent No. 9802648-7 (SE512 433) and the quality can be improved by utilizing the possibility to classify coarse particles larger than 5 xcexcm to leave those out and dose only fine particles (less than 5 xcexcm) onto the device member or cassette as described in our Swedish Patent No. 9802649-5 (SE512 386).
The term electro-powder refers to a micronized medical powder presenting controlled electrostatic properties to be suitable for electrostatic administration in an inhaler device. Such an electro-powder provides possibilities for a better dosing from electrostatically operating equipment such as disclosed in our U.S. Pat. No. 6,089,227 as well as our Swedish Patents No. 9802648-7 and 9802649-5, which present excellent inhalation dosing performance.
One major problem is to obtain a low relative standard deviation (RSD) between doses with this type of technique due to lack of in line control possibilities in production making it hard to be in compliance with regulatory demands. For electrostatically dosed medical substances the relative standard deviation between doses (RSD) should preferably be not more than  less than 5%. For a prior art DPI the fine particle fraction and uniformity of dose together with the user dependency is a major drawback and this can be seen in a document by D. Prime, A. C. Grant, A. L. Slater and R. N. Woodhouse, xe2x80x9cA Critical Comparison of the Dose Delivery Characteristics of Four Alternative Inhalation Devices Delivering Salbutamol: Pressurized Metered Dose Inhaler, Diskus Inhaler, Diskhaler Inhaler, and Turbuhaler Inhalerxe2x80x9d, Journal of Aerosol Medicine, Volume 12, Number 2, 1999, pp 75-84, Mary Ann Liebert, Inc.
Devices of prior art technology does often not reach a sufficiently high degree of de-agglomeration and an exact dose is not well developed and leaves much to be desired when it comes to dosage conformity and lung deposition effectiveness of the medical substance.
This means there is still a demand for a dry powder inhaler in which the important functions have been optimized to give a very high de-agglomeration, meaning a high fraction of particles under 5 xcexcm for local lung and under 3 xcexcm for deep lung and a uniformity of dose that is independent of minor variations in the user""s inhalation.
A method and a process are disclosed for optimizing an electrostatically dosed dry powder inhaler (EDPI) for utilization of a prepared pre-metered electro-dose consisting of a electro-powder. An arrangement is set-up for measuring parameters affecting a systemic delivery or local lung delivery of a pre-metered electro-dose from and DPI including analysis of dose de-agglomeration, particle size distribution as well as dose-to-dose variation together with pressures times and flows. A dry powder inhaler, DPI, is adjusted for a systemic or a local lung setting with respect to activation pressure and closing pressure having a DPI with a 20 to 60 liters/minute inhalation air flow for systemic delivery setting and 20 to 80 liters/minute for a local lung setting. Furthermore the de-agglomeration power is adjusted between 0.1 and 6 watts to be used in the DPI by optimizing the pressure drop and inhalation flow rate by changes to the mouthpiece and/or the device member and their relation to each other. The DPI activation pressure is further adjusted to a value between 0.5 and 4 kPa and closing pressure between 0.5 and 4 kPa to eliminate the low power at the start and end of the inhalation. The method and process then verify that the DPI meets the set specification regarding de-agglomeration power and opening and closing pressures. Furthermore is verified that de-agglomeration difference, expressed in percent using an expression 100[1xe2x88x92de-agglomeration(Q1 kPa)/de-agglomeration(Q)], is not more than 50%. Finally if the DPI is not approved as an EDPI the tested DPI and/or electro-dose is further adjusted to check if the DPI can meet the specification of an EDPI.